Cook, Light, Light, Broderick et al: Neural Consequences of Post-Exertion Malaise in ME/CFS

[A.B.]

I think you will be surprised when the true mechanism of this illness comes into light and we find out what is driving the biochemical, hormonal and cellular changes in the bodies of ME patients. I am thinking it has to do with what controls and oversees the function of the Endocrine System and especially the Pituitary, Pineal and Adrenal Glands.

The metabolomics studies seem to suggest that the problem could be very simple: something in the serum preventing normal energy metabolism, which could easily explain many symptoms.

The Rituximab studies suggest that there's autoimmunity.

It would make sense if the antibody was responsible for the energy metabolism problems. The subtle dysregulation of important body systems that is commonly found in patients might be an adaptation to chronic energy deficits, some Dauer-like state.

How do you reconcile the metabolomic and Rituximab results with disturbance of the endocrine system? The endocrine system works through hormones right? Is factor x in the serum that's causing energy dysfunction some hormone that science hasn't discovered yet? Because the hormones we know about have been measured in patients and nothing is sufficiently abnormal to explain the high level of impairment. If the presumed autoimmunity is targeting parts of the brain involved in the endocrine system then that would be visible on hormone tests.

 

[Mohawk1995]

@A.B. That is a very logical response and yes I question my own thoughts at times which I think is a good thing.

To be honest my area of expertise is definitely not in the Endocrine functions, but here is my best to respond.

Because there is something in the Blood serum according to metabolomics, hormones from the endocrine system could certainly play a role as the circulatory system is the its "preferred" transportation system. Secondly the influence that the endocrine system has on energy production within the body seems a potential key point. The Endocrine system is both overseen by and creates influences on the really big player in the equation...Neurophysiology. Is it an as yet to be determined substance/hormone? Is it a yet to be discovered neurotransmitter? Is it due to a combination of factors including hormonal and neurotransmitter? Great questions that I do not have the answer to. Also then what role does Neuro-inflamatory processes play since that is a marker that has been identified as well? Then yes there is the auto-immune factor which of course just makes it that much more difficult to figure out.

I am in the camp of those who think that MEs origin is Neurophysiological in nature, but I have no substantiated proof it is. It just seems to fit all that I know about human physiology which is admittedly limited especially in some areas. The problem with some considering my viewpoint is that they think Neurophysiology is primarily conscious when anatomically and physiologically that has been clearly dis-proven.

Perhaps you are able to take my thoughts and make them more sensible. That would be more than welcome.

 

[Research 1st]

One thing I was thinking thinking of hypometabolism, glycolosis etc.....


Observation regarding utilization of glucose: Some CFS patients must have glucose (soda) every few hours or they 'freak out ' like having a partial first stages of a hypoglycemia event (probably as our brain glucose is low, but our peripheral blood is low normal). Yet, other patients hate sugar and avoid it as it makes them worse (likely different patient subsets).

So I really hope biomedical CFS researchers learn about phenomena such as this and run these metabolic tests on CFS patients regarding things like Pyruvate and related mitchondrial assays both fasting and non fasting. I think reserachers have all overlooked this, the huge differences we all have as patients regarding how we deal with carbohydrates metabolically and endocrinologically yet we all share the same label of 'CFS'.

In my view, it's critical as researchers begin to get closer to the holy grail of answer, that the wrong CFS patient subsets don't end up in the right CFS subset study that should have been successful, and vice versa, as then both patient groups may suffer as research may come to a dead end or result in confusing result that to researchers make no sense, but to us the patients, make perfect sense.

If we allow this to happen (not make researchers aware we have totally opposing reactions to sugar, and lack of artificial power tanks (e.g. when we stop eating carbs) by then, the grant money has been spent, time wasted and its too late to repair mistakes as funds are so limited.

This really worries me. You could argue I should chill out and it's just a 'severe' ME effect (e.g. low blood sugar 'like' events - are actually low brain cortisol/undiagnosed adult GH deficiency as a secondary effect of chronic severe ME), but what if it's not? What if there really are two opposing metabolic effects affecting glycolosis and we are on the cusp of proving this in 2018 but in larger studies (e.g. 400 people) by statistical fluke 78% of Group A are included, 22% of Group B, when the effect researchers wanted to measure, was Group B alone. The paper then fails, and everything is forgotten about.

Conundrum in CFS biological research:

How do we make sure biomedical CFS researchers can guard against this potential issue described above (Group A Vs B example), if the 'rules' of CFS research the government accept is the patients you get blood from simply meet Fukuda CFS criteria which means they are CFS patients by diagnosis of exclusion, not inclusion. E.g. if we intentionally 'discriminate' (select patients we know have the defect) people will cry and say hey, these guys don't have CFS then as you no longer selected people in your study as they didn't have unexplained chronic fatigue - an impossible measure (fatigue) to ever prove the causation of universally, hence the inventors of CFS (CDC) should be given an award for reckless stupidity in naming our disease 'CFS' in the first place, as it'll only ever make finding the cause impossible. So lets not get stuck in this trap to begin with.....

For our disease to be detected successfully by honest and expert scientists, we need to turn it into a disease of inclusion, by including defects X,Y,Z before, not after the research is performed - yet Fukuda CFS criteria doesn't allow for this!

Catch 22 - Necessity of filtering out the 'wrong subsets' (non organic chronic fatigue) from your disease within a soup of unrelated fatigue disorders.

The only thing I can think of is for biological CFS researchers to understand this NOW, and say OK then, we'll use far stricter criteria (ME-ICC) or drop the title CFS entirely and go for ME when we publish the paper, to stop any ''but they don't have CFS'' arguments - which are really important as they stop you getting more 'CFS' funding for follow up studies. We know this is precisely what the psych lobby will do, who are waiting in the wings to pounce once ANY biomarker is discovered and pinned on 'CFS'. Their psych CFS patients won't test positive and game over.

Another Catch 22 - Necessity of not publishing your game changing paper as 'CFS' in the title by being fully aware that so many weak criterias are in use for CFS (including Oxford F48.0 the UK MRC use), that others can destroy the validity of your paper by simply choosing Fukuda CFS or worse, and finding nothing.

 

[Valentijn]

Just because something is Neurophysiological does not mean it is Psychological or Conscious.

First of all, the diseases you listed are not all substantially neurological. Additionally, you've left out a great many diseases which are neurological, such as MS. What the listed diseases have in common is that their etiology is unknown, and they are accordingly considered up for grabs by the quacks.

The notion of "psychosomatic" is physiological child's play compared to the functions I am referencing.

I suspect this ties into your unfounded belief in central sensitization. Again, this is just the current fad in saying "psychosomatic", with a thin veneer of pseudoscience on top in an attempt to make it more palatable. We do not have central sensitization. The other diseases you listed also do not have central sensitization. If you're going to use the concept in a supposedly scientific way, there's going to need to be some actual science behind it first - and there isn't.

I am thinking it has to do with what controls and oversees the function of the Endocrine System and especially the Pituitary, Pineal and Adrenal Glands.

Unlikely. If you were familiar with ME research, you'd know this was also a psychosomatic quack fad about 20 years ago. They've largely given up on it, as the science once again contradicted the theory, and they had to invent a new pseudoscientific explanation to support GET and CBT as treatments.

 

[A.B.]

Also then what role does Neuro-inflamatory processes play since that is a marker that has been identified as well?

I don't know how subtle neuroinflammation would fit in. It could be a consequence of a messed up gut which could be either due to changes in immune system or hypometabolism in digestion related pathways (I believe alteration in bile acids were observed in one metabolic study). The vague nerve could play important play a role in "transmitting dysfunction" from the gut to the rest of the nervous system. Not sure if that makes sense.

 

[Mohawk1995]

@A.B. Yes that makes sense to me and adds additional dimensions I had not fully considered. I think the vagus nerve likely plays a big role in what we see in ME.

@Valentijn Your insistence on discounting the role Neurophysiology plays in ME is understandable when taking into account your belief that all Neurophysiology is somehow directly tied to Psychosomatic disorders. This is not in line with current Neuroscience Research which is even this very day finding more support for the fact that 90% of neurological functions are NOT Conscious or even under "Subconsious" control.

In addition, your insistence that Biochemical, metabolic, immune and basically every biomolecular system in the body are not under either direct or indirect control of the Nervous system (in particular the Central Nervous System) is antiquated thought. They cannot be so easily separated as you suggest. So when I see mud in the water (biochemical, metabolites, autoimmune markers), I look upstream (Central Neural Process that oversee and control the release and levels of these agents).

I am not thinly veiling Psychosomatic or supporting CBT or GET as a primary treatment for ME. Never have. In fact during my son's primary treatment he was told absolutely no exercise. We followed the doctor's orders explicitly and for him it worked. Why would I now advocate something different?

PS Science (especially medical) is a funny thing. It is often swayed way more by bias and opinion than most are willing to admit. In addition, everyone including you and I are looking for evidence to support our view. The first step in good science is acknowledging our bias. The second is questioning everything with the first step in mind. Dr Davis and others
like him appear to do this. But again, I am critical in general when it comes to any research.

 

[HowToEscape?]

One thing I was thinking thinking of hypometabolism, glycolosis
......

In my view, it's critical as researchers begin to get closer to the holy grail of answer, that the wrong CFS patient subsets don't end up in the right CFS subset study that should have been successful, and vice versa, as then both patient groups may suffer as research may come to a dead end or result in confusing result that to researchers make no sense, but to us the patients, make perfect sense.
.......

Conundrum in CFS biological research:

chronic fatigue - an impossible measure (fatigue) to ever prove the causation of universally, hence the inventors of CFS (CDC) should be given an award for reckless stupidity in naming our disease 'CFS' in the first place, as it'll only ever make finding the cause impossible. So lets not get stuck in this trap to begin with.....

For our disease to be detected successfully by honest and expert scientists, we need to turn it into a disease of inclusion, by including defects X,Y,Z before, not after the research is performed - yet Fukuda CFS criteria doesn't allow for this!........

Another Catch 22 - Necessity of not publishing your game changing paper as 'CFS' in the title by being fully aware that so many weak criterias are in use for CFS (including Oxford F48.0 the UK MRC use).......

(Quoted post snippets)

Determining the exact criteria for inclusion will be a little tricky. Many of us clearly have the disease overall but do not satisfy one or another official symptom criteria, while having other related symptoms which are not in any of the publicized definitions. PEM seems to be the closest to a universal common element, but then the definition of exertion commonly used is wrong: it's not watt-hours of output on the stationary bike, it's nearly any demand on the system.

I get a worse crash from standing in line than from several times as many calories expended on a stairmaster (I suspect the pumping action is helping blood and oxygen get where it needs to be, which somehow offsets the crash mechanism).** I will get an even worse crash from attending any type of social event, unless it is lying on the floor. But I have only slight headaches and no joint or muscle pain, & no sore throat. Whoever wrote the criteria doesn't know the patients.

**Just to be clear I avoid standing in long lines, and haven't been on the stairmaster in years. But I would take a chance on the latter in small doses as it has health benefits as well as some cost, while the former has zero benefit and worse health cost, in my experience so far.

 

[Tom Kindlon]

https://twitter.com/i/web/status/856269240957112328

https://twitter.com/i/web/status/856270544483864576

https://twitter.com/i/web/status/856271345478512640

 

[Tom Kindlon]

https://twitter.com/i/web/status/853141961263415296

 

[Dolphin]

Cognitive performance generally improved for controls both during scanning and from pre- to post-exercise. The opposite occurred for ME/CFS with a worsening of performance (i.e. greater errors) across blocks during scanning, as well as from pre- to post-exercise.

 

[Dolphin]

3.9. Relationships between PASAT brain responses and symptoms of PEM

Self-reported fatigue (POMS) following exercise was significantly and positively related to brain responses in the right inferior parietal and superior temporal cortices for ME/CFS patients (184 voxels; p < 0.05corrected – See Fig. 7). In addition, self-reported muscle pain post-exercise was positively and significantly related to activity within the left inferior frontal cortex (102 voxels; p < 0.05corrected). For controls, self-reported fatigue was significantly and negatively related to activity within the right inferior parietal cortex (120 voxels; p < 0.05corrected) and this relationship was significant different than that observed in the ME./CFS group. No other significant relationships were found for the subscales of the POMS or other CDC VAS ratings.

We also examined the relationship between total errors on the PASAT and brain activity. For ME/CFS patients, errors were significantly and negatively related to activity within the left inferior parietal cortex (369 voxels; p < 0.05corrected), as well as, bilateral superior temporal cortices (left: 156 voxels, right: 124 voxels; p < 0.05corrected). For controls, errors were significantly and positively associated with activity within the mid- and posterior cingulate cortices (167 voxels; p < 0.05corrected).

 

[Dolphin]

Our results demonstrated that for ME/ CFS patients acute exercise exacerbated numerous symptoms, impaired cognitive performance and affected brain function. These converging results, linking behaviors associated with PEM to brain function, illustrate some of the potential detrimental effects of PEM and provide additional support for central nervous system dysregulation in the pathophysiology of ME/CFS.

 

[Dolphin]

Our results suggest that PEM negatively affects executive function in ME/CFS with greater errors during the PASAT as a consequence. The significant and positive relationship with self-reported muscle pain suggests that those ME/CFS patients with the most pain symptoms required greater recruitment of executive control processes to perform the PASAT or that muscle pain interfered with the top-down control during performance of a demanding cognitive task.

 

[Dolphin]

For ME/CFS patients, activity in the parietal regions was positively related to self-reported fatigue and difficulty concentrating, but only post exercise when symptoms were exacerbated.

 

[Dolphin]

An important aspect of this study is that brain responses in ME/ CFS patients were significantly related to symptoms of PEM – including fatigue, pain and difficulty concentrating.

 

[Dolphin]

One of the more striking findings was the magnitude of the reduction in brain responses during the PASAT for the controls from pre- to post-exercise. White and colleagues Reductions in brain responses occurred within multiple regions including parietal, temporal and frontal cortices and suggest that the controls required less neural resources to quickly and accurately perform the serial addition task. ME/CFS patients did not demonstrate any significant reductions in brain responses during the PASAT and instead showed significant increases in both inferior and superior parietal cortices post-exercise. These results provide objective evidence that for ME/CFS, PEM affects cognition, having widespread effects on brain regions associated attention, working memory and executive function. The pre- to post-exercise reductions in brain activity for controls were also associated with improved cognitive performance (i.e. reduced errors), which may reflect further practice effects or greater comfort within the neuroimaging environment. Because ME/CFS patients responded opposite to controls, having greater brain activity, reduced cognitive performance and increased symptoms post-exercise, these results emphasize the strong negative impact that PEM can have on the central nervous system.

 

[Dolphin]

In the present study, group differences in the pattern of cognitive performance were clear. ME/ CFS patients showed increasing errors as a function of both within-in task performance (i.e. increasing errors with time-ontask) and as a function of acute exercise (i.e. greater errors 24 h post-exercise). Controls showed significantly different and characteristically opposite responses that were reflective of the neuroimaging data. In general, controls improved as a function of time-on-task and continued to improve 24-h post-exercise. Physiologically, this was represented by reduced brain activity among multiple cognitively-relevant brain regions following exercise.

 

[Dolphin]

Overall, this study’s findings emphasize the importance of symptom provocation in the study of ME/CFS by demonstrating significant and characteristically opposite brain and behavioral responses in patients compared to controls – providing evidence that acute exercise can negatively impact neurophysiological processes in ME/CFS. These findings also provide objective evidence for the subjective experience of cognitive symptoms (i.e. brain fog) reported by ME/CFS patients when they attempt to be physically active.